p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease

Chen, Jialong; Mao, Kanmin; Yu, Honglin; Yue, Wen; She, Hua; Zhang, He; Li, Mingque; Li, Wenjun; Zou, Fei

doi:10.1186/s12974-021-02349-y

Cited by 45 publications

(40 citation statements)

References 44 publications

(38 reference statements)

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“…MAP kinases are important contributors to pain sensitization after nerve injury [ 49 ]. A potential interaction between MAP kinase signaling and αSyn has already been described, with overexpression of αSyn associated with upregulation of p38 and p42/44 activity [ 50 , 51 , 52 ]. In addition, inhibition of p38 was linked to protective effects in PD and to a decrease in microglia activation [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…A potential interaction between MAP kinase signaling and αSyn has already been described, with overexpression of αSyn associated with upregulation of p38 and p42/44 activity [ 50 , 51 , 52 ]. In addition, inhibition of p38 was linked to protective effects in PD and to a decrease in microglia activation [ 51 ]. Therefore, downregulation of MAPK activation in Snca knock-out mice after nerve injury associated with decreased mechanical allodynia in our study fits very well with the already published data.…”

Section: Discussionmentioning

confidence: 99%

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The Role of AlphαSynuclein in Mouse Models of Acute, Inflammatory and Neuropathic Pain

Möller

Möser

Weiß

et al. 2022

Cells

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(1) AlphαSynuclein (αSyn) is a synaptic protein which is expressed in the nervous system and has been linked to neurodegenerative diseases, in particular Parkinson’s disease (PD). Symptoms of PD are mainly due to overexpression and aggregation of αSyn and include pain. However, the interconnection of αSyn and pain has not been clarified so far. (2) We investigated the potential effects of a αSyn knock-out on the nociceptive behaviour in mouse models of acute, inflammatory and neuropathic pain. Furthermore, we assessed the impact of αSyn deletion on pain-related cellular and molecular mechanisms in the spinal cord in these models. (3) Our results showed a reduction of acute cold nociception in αSyn knock-out mice while responses to acute heat and mechanical noxious stimulation were similar in wild type and knock-out mice. Inflammatory nociception was not affected by αSyn knock-out which is also mirrored by unaltered inflammatory gene expression. In contrast, in the SNI model of neuropathic pain, αSyn knock-out mice showed decreased mechanical allodynia as compared to wild type mice. This effect was associated with reduced proinflammatory mechanisms and suppressed activation of MAP kinase signalling in the spinal cord while endogenous antinociceptive mechanisms are not inhibited. (4) Our data indicate that αSyn plays a role in neuropathy and its inhibition might be useful to ameliorate pain symptoms after nerve injury.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Role of AlphαSynuclein in Mouse Models of Acute, Inflammatory and Neuropathic Pain

Möller

Möser

Weiß

et al. 2022

Cells

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“…The microglia possess an immune function and secrete pro-inflammatory cytokines. According to the functions of microglia in the neuroinflammation, they can be categorized into two groups: poisonous to nerves (M1-phenotype microglia) and protective to nerves (M2-phenotype microglia) (Biondetti et al, 2021;Chen et al, 2021). Activated microglia secrete interleukin-1α (IL-1α), tumor necrosis-α (TNF-α), and C1q, the first subcomponent of the C1 complex, which induce astroglia into A1s (Cheng et al, 2021).…”

Section: Gliamentioning

confidence: 99%

The Mechanism and Function of Glia in Parkinson's Disease

Zhang

Awan

et al. 2022

Front. Cell. Neurosci.

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Parkinson's disease (PD) is a neurodegenerative disease that primarily affects elderly people. The mechanism on onset and progression of PD is unknown. Currently, there are no effective treatment strategies for PD. PD is thought to be the loss of midbrain dopaminergic neurons, but it has recently been discovered that glia also affects brain tissue homeostasis, defense, and repair in PD. The neurodegenerative process is linked to both losses of glial supportive-defensive functions and toxic gain of glial functions. In this article, we reviewed the roles of microglia, astrocytes, and oligodendrocytes in the development of PD, as well as the potential use of glia-related medications in PD treatment.

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“…In addition, lysozyme 2Cre (Lyz2cre)-mediated deletion of microglial autophagy-related gene 5 (ATG5) aggravates neuroinflammation and loss of dopaminergic neurons in the substantia nigra and aggravates the loss of α-synuclein overexpressing mice ( Tu et al, 2021 ). In addition, α-Syn leads to microglial activation by activating TLR4 and its downstream p38 and Akt-mTOR signaling ( Chen et al, 2021 ). Miki et al (2018) found that the autophagy core regulator genes ULK3, Atg2A, Atg4B, Atg5, Atg16L1, and histone deacetylase six mRNAs were downregulated when they studied the peripheral blood mononuclear and cell-based autophagy of Parkinson’s patients, and the autophagy protein ULK1 was downregulated, Beclin1 protein levels were significantly increased, and the mRNA expression of these proteins was negative feedback and correlated with increased α-synuclein levels.…”

Section: Interaction Between Autophagy and Nlrp3 Inflammasome In Neur...mentioning

confidence: 99%

Interaction between autophagy and the NLRP3 inflammasome in Alzheimer’s and Parkinson’s disease

Zhang

Yang

2022

Front. Aging Neurosci.

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Autophagy degrades phagocytosed damaged organelles, misfolded proteins, and various pathogens through lysosomes as an essential way to maintain cellular homeostasis. Autophagy is a tightly regulated cellular self-degradation process that plays a crucial role in maintaining normal cellular function and homeostasis in the body. The NLRP3 inflammasome in neuroinflammation is a vital recognition receptor in innate cellular immunity, sensing external invading pathogens and endogenous stimuli and further triggering inflammatory responses. The NLRP3 inflammasome forms an inflammatory complex by recognizing DAMPS or PAMPS, and its activation triggers caspase-1-mediated cleavage of pro-IL-1β and pro-IL-18 to promote the inflammatory response. In recent years, it has been reported that there is a complex interaction between autophagy and neuroinflammation. Strengthening autophagy can regulate the expression of NLRP3 inflammasome to reduce neuroinflammation in neurodegenerative disease and protect neurons. However, the related mechanism is not entirely clear. The formation of protein aggregates is one of the standard features of Neurodegenerative diseases. A large number of toxic protein aggregates can induce inflammation. In theory, activation of the autophagy pathway can remove the potential toxicity of protein aggregates and delay the progression of the disease. This article aims to review recent research on the interaction of autophagy, NLRP3 inflammasome, and protein aggregates in Alzheimer’s disease (AD) and Parkinson’s disease (PD), analyze the mechanism and provide theoretical references for further research in the future.

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p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease

Cited by 45 publications

References 44 publications

The Role of AlphαSynuclein in Mouse Models of Acute, Inflammatory and Neuropathic Pain

The Role of AlphαSynuclein in Mouse Models of Acute, Inflammatory and Neuropathic Pain

The Mechanism and Function of Glia in Parkinson's Disease

Interaction between autophagy and the NLRP3 inflammasome in Alzheimer’s and Parkinson’s disease

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